Many medical agents are administered to a patient for achieving a desired biological effect at one or more tissues. Often the therapeutic effect of the administered substance is accompanied by toxic effects. Toxic effects may be immediate or delayed, acute or chronic, or any combination of these. The toxic effects may include, but are not limited to, radiation exposure, immunization to the substance, alteration of normal metabolic function, specific tissue damage, and other diverse and/or idiosyncratic symptoms.
Medical agents are also administered for the purpose of diagnosing diseases. The time span during which the agents are effective for this purpose is often limited. The relative effectiveness of the administered agent as a diagnostic agent can also be limited by the relative specificity of targeting of that agent to specific tissues in the body. Removal of the administered substances can often enhance the effectiveness of the substance.
The present invention discloses a method for the treatment of a patient with a wide variety of medical agents for therapeutic or diagnostic purposes. The common element that defines the group of medical agents included within the scope of this invention is that they all, for a variety of reasons, reach a certain point in time after the initial treatment when their continued existence in the patient's body is no longer desirable, and is generally harmful. In some cases, the circulating medical agent is toxic to the body. In other circumstances, the medical agent itself is not toxic, but the bodies mechanism for clearing the agent may be harmful to the body. In many cases the agent will accumulate, in equilibrium with circulating concentrations of the agent, in certain tissues in the body. In these cases, the agent's toxicity is localized to these tissues.
The method of the present invention encompasses the treatment of a patient with a medical agent and the subsequent selective extracorporeal removal of that agent from the patient's body. Although the extracorporeal removal of agents from patients is a well-known procedure, its combination within an integrated treatment scheme has heretofore not been described.
In a treatment scheme somewhat related to the method of the present invention, there has been described a procedure that begins with the introduction of foreign proteins into the body of a patient. These foreign, or exogenous, proteins may be immunotoxins that are introduced into the patient in order to immunologically attack an undesirable element in the patient's body. In time, the presence of the exogenous protein generates, via the patient's immune system, antibodies to the exogenous proteins. The presence of the antibodies will effectively neutralize the beneficial effects of the exogenous protein.
U.S. Pat. Nos. 4,865,841 and 4,801,449 of Balint, Jr. et al. and 4,215,688 of Terman et al. each describe a treatment procedure whereby the endogenously produced antibodies are removed from a patient via selective extracorporeal treatment. In each of these cases, an immunoadsorption column is prepared by covalently binding a material that will selectively immobilize the endogenous protein from the blood plasma. Since the endogenous protein which is to be removed is the antibody to the originally administered exogenous protein, selective immunoadsorption can be achieved by bonding the exogenous protein to the column material. The critical distinction between the present invention and the procedures described by Balint, Jr. and Terman is that in these procedures the agent or protein being selectively extracorporeally removed from the patient is not the same agent with which the patient is being treated, but an endogenously produced material generated by the body in response to the exogenous medical agent. Also see U.S. Pat. No. 4,838,852 of Edelson et al for a related system.
In U.S. Pat. Nos. 4,375,414, 4,620,977, 4,834,973 and 4,813,924 of Strahilevitz there is described a procedure for the extracorporeal removal of psychoactive drugs from the blood stream. Again, immunoadsorption columns are described which will selectively remove the target drug from the blood stream in an extracorporeal manner. Although this procedure involves the extracorporeal removal of exogenous materials from a patient, it is not in any way part of an integrated treatment or diagnostic method. It is assumed that these methods are directed to the rescue of patients who have taken potentially harmful quantities of these non-therapeutic and non-diagnostic drugs.
U.S. Pat. Nos. 4,824,432, 4,605,394, and 4,362,155 of Skurkovich et al. describe methods for the treatment of pathological conditions connected with the production of interferons which destroy the immune system. In one embodiment, the endogenously produced interferons are removed by extracorporeal perfusion of a patient's blood. Again, these disclosures do not relate to an integrated treatment where medical agents are administered to a patient for therapeutic or diagnostic purposes and then removed from the patient by selective extracorporeal means in order to prevent harmful effects to the patient caused by the long-term presence of the exogenous agent. Also see U.S. Pat. No. 4,925,920 of Mannick et al.
In U.S. Pat. No. 4,800,016 of Yang, an extracorporeal system for the treatment of blood is described. The invention of the Yang patent is employed in medical procedures where blood is processed in an extracorporeal device, such as an artificial kidney or heart-lung machine, and the blood is heparinized to prevent clotting within the channels of the extracorporeal device. Traditionally, after heparin-containing blood has been treated in such extracorporeal devices protamine is added to the blood prior to its reintroduction into the body to negate the anti-coagulating effects of the heparin. In the Yang method, the heparin is selectively eliminated from the blood stream by passing it through a support that contains covalently-bonded protamine. By this means the heparin is actually removed from the bloodstream rather than just having its effects negated.
Yang differs from the present invention in that the heparin is not administered to a patient, but is merely part of the extracorporeal treatment of the patient's blood. The heparin does not provide a therapeutic or diagnostic benefit to the patient, but merely acts to facilitate the already extracorporeal blood supply treatment. A analogous method is described in U.S. Pat. No. 4,863,611 of Bernstein, et al., wherein heparinase, immobilized on agarose beads, is used to remove the heparin from the blood prior to its reintroduction into the patient.
The immobilization of immunochemicals for use in selective separation procedures is well known. Methods for the preparation of cellulose or agarose supports that contain covalently bonded molecules, such as antibodies, are commercially available. These immobilized materials have occasionally been used in extracorporeal systems for the removal of specific materials from blood plasma. See, for example, U.S. Pat. No. 4,846,786 of Freed et al.
A related technology is described in U.S. Pat. No. 4,877,599 of Lees. Lees describes a method for the detection of vascular disease by administering to a patient a conjugate diagnostic reagent. The conjugate reagent includes a target-seeking biologically active molecule and labelling means for extracorporeal detection. The method does not include the extracorporeal removal of the administered reagent.
In a similar scheme, U.S. Pat. No. 4,863,713 of Goodwin et al. describes a system for localizing a diagnostic or therapeutic agent to an internal target site. The system includes an epitopic compound, a binding protein that will direct the compound, and a clearing agent which will form a protein aggregate which is readily cleared from the patient's blood.
Extracorporeal systems for the treatment of bodily fluids are well known. In general, blood is removed from the patient and separated into plasma and blood concentrate streams. Extracorporeal treatment is almost always more effective when treating the plasma stream. After chemical modification or treatment is performed, the blood is returned to the patient.
There are several instances where the optimal treatment of a patient with a medical agent for therapeutic or diagnostic procedures would include artificial or extracorporeal rescue. Nearly all administered medical agents will ultimately be cleared from the body. Generally, compounds are cleared by the functions of the liver, spleen and kidneys and the reticuloendothelial system. However, clearance can also involve immunological immobilization and degradation. Some medical agents also will accumulate in certain tissues in the body for relatively long periods of time. This invention encompasses treatments with therapeutic or diagnostic agents wherein it would be desirable to remove or drastically diminish the amount of such agents from the body before the agents would be cleared by the body under normal circumstances.
One example of a suitable medical agent system is the administration of radiolabeled antibodies to cancer patients for the purpose of diagnosing tumors and/or for therapeutic treatment of tumors. The treatments involve injection of a radiolabeled monoclonal anti-tumor antibody which has a binding specificity for molecules primarily restricted to tumor cells.
Conventional radiation therapy is a highly effective modality in the treatment of cancer. One of the severe limitations of the procedure is normal tissue tolerance to the radiation. In particular, bone marrow toxicity is the limiting factor in determining radiation dosages. In recent years, advances have been made so that it is now possible to design and create tumor-specific or tumor-related antibodies that are labeled with a radioactive substance such as .sup.131 I. See, for example, Maners et al., Annals of Clincal and Laboratory Science, 1988, Vol. 18, pp. 53-57.
Several .sup.131 I labeled antibodies have been prepared in attempts to maximize the localization of the radioactive material at the tumor site. Obviously, this procedure can be valuable for both therapeutic and diagnostic purposes.
For either purpose, the treatment of cancer patients with radiolabeled antibodies has been plagued by several problems. Foremost among these problems is the lack of specificity of the antibodies to the tumor. While a significant amount of the monoclonal antibody is localized at tumor cells, the amount of monoclonal antibody localized is usually only a small percentage of the total administered dose. A large amount of monoclonal antibody will, therefore, localize to the lungs, liver, spleen and bladder as well as to other organs, or exist in the circulation system until cleared by natural mechanisms.
Improved localization would greatly improve the treatment of cancer with monoclonal antibodies for two reasons: 1) It would allow an improved signal-to-noise ratio which would allow better imaging of some tumors and recognition of previously undetected tumors; and 2) It would allow a decrease in the total body irradiation and/or a decrease in a specific organ irradiation which occurs as an undesired result of the unbound or circulating monoclonal antibody.
Tumor site localization could be artificially improved by a procedure that would eliminate "circulating" monoclonal antibodies from a patient prior to the normal clearance. Advances in the development of radiolabeled delivery agents have often focused on increasing the lifetime of the agent in the patient in order to assure that the agent is given sufficient time to reach its desired location. In engineered agents which have greatly increased circulating half-lives, the ability to remove the agent from the blood stream would be even more critical.
A variety of strategies to improve tumor localization of injected labeled monoclonal antibodies have been attempted. In Sharkey et al., Cancer Research, 1988, Vol. 48, pp. 2005-2009, the authors state:
Radiolabeled antibodies have proven their usefulness in the early detection of cancer by external scintigraphic imaging . . . However a major problem of radiolabeled immunodetection is the persistence of high levels of blood pooled radioactivity that increases the difficulty in identifying specific antibody accretion in tumor.
Attempts at resolving this problem are described, for example, in the following additional references: Wahl et al., Nucl. Med. Biol. 1987, Vol. 14, pp. 661-615; Wahl et al., Cancer Immunol. Immuno. Ther., 1988, Vol. 26, pp. 187-201; Begent et al.; The Lancet, Oct. 2, 1982; Spies et al., Seminars in Nuclear Med., 1987, Vol. 17, pp. 267-272; Paganelli et al., Int. J. Cancer: Supplement 2, 1988, pp. 121-125; Meeker et al., Blood, 1985, Vol. 65, pp. 1349-1363; Vacca et al., Cancer, 1988, Vol. 61, pp. 58-67; and Munz et al., J. Nucl. Med., 1986, Vol. 27, pp. 1739-1745.
The therapeutic and diagnostic uses of radiolabeled monoclonal antibodies in cancer treatment is just one example of a medical agent treatment where it would be desirable to eliminate circulating levels of the medical agent more rapidly than the normal body clearance process. It need not be that the existence of the medical agent causes direct harm to a patient, but it may also be desirable in maximizing the therapeutic or diagnostic benefit hoped to be obtained from the medical agent or of another related or unrelated therapeutic or diagnostic procedure. The present invention provides an attractive and useful approach to address all of these needs.